Cd47-Sirpα interaction and IL-10 constrain inflammation-induced macrophage phagocytosis of healthy self-cells
Cd47-Sirpα interaction and IL-10 constrain inflammation-induced macrophage phagocytosis of healthy self-cells
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DOI：
10.1073/pnas.1521069113
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发表时间：
2016-09-13
影响因子：
11.1
通讯作者：
Liu, Yuan
中科院分区：
文献类型：
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作者：
Bian, Zhen;Shi, Lei;Liu, Yuan
CD47(-/-)是一种关键的自我识别机制，它与巨噬细胞信号调节蛋白α(SIRPα)相互作用，通过SIRPα胞浆免疫受体酪氨酸抑制基序和酪氨酸磷酸酶SHP-1/2激活抑制信号。然而，CD47(-/-)小鼠并不表现出自毁表型，而是没有或仅表现出轻微的巨噬细胞吞噬自我细胞，除非在非肥胖的糖尿病背景下。研究我们最近建立的SIRPα-KO(Sirpa(-/-))小鼠，以及CD47(-/-)小鼠，我们揭示了除了CD47-SIRPα轴主要控制巨噬细胞行为之外，其他激活和抑制机制。Sirpa(-/-)小鼠和CD47(-/-)小鼠虽然正常，但在慢性结肠炎、腹膜炎、细胞因子治疗和CFA-/LPS诱导的炎症下，由于脾巨噬细胞吞噬自身红细胞，会发生严重的贫血和脾肿大。体外吞噬试验证实，来自SIRPα(-/-)或CD47(-/-)小鼠的巨噬细胞对健康的自体细胞普遍缺乏活性，而它们对细菌、酵母多糖、凋亡和免疫复合物结合的细胞具有攻击性；然而，用IL-17、LPS、IL-6、IL-1β和肿瘤坏死因子α处理这些巨噬细胞，而不处理干扰素γ，显著地启动对自身细胞的强大吞噬，这只有CD47-Sirpa相互作用受到抑制。即使是来自WT小鼠的巨噬细胞，在没有吞噬激活的情况下，也不会对CD47(-/-)细胞进行吞噬。机制研究表明，激活巨噬细胞的自身靶向性需要一条PKC-Syk介导的信号通路，而IL-10反过来抑制该通路，随后吞噬作用不依赖于钙网蛋白。此外，我们发现，尽管CD47(-/-)或SIRPα(-/-)小鼠缺乏，但脾红髓是一种特殊的组织，可以提供持续激活巨噬细胞吞噬功能的刺激。
Rapid clearance of adoptively transferred Cd47-null (Cd47(-/-)) cells in congeneic WT mice suggests a critical self-recognition mechanism, in which CD47 is the ubiquitous marker of self, and its interaction with macrophage signal regulatory protein alpha (SIRP alpha) triggers inhibitory signaling through SIRP alpha cytoplasmic immunoreceptor tyrosinebased inhibition motifs and tyrosine phosphatase SHP-1/2. However, instead of displaying self-destruction phenotypes, Cd47(-/-) mice manifest no, or only mild, macrophage phagocytosis toward self-cells except under the nonobese diabetic background. Studying our recently established Sirp alpha-KO (Sirpa(-/-)) mice, as well as Cd47(-/-) mice, we reveal additional activation and inhibitory mechanisms besides the CD47-SIRP alpha axis dominantly controlling macrophage behavior. Sirpa(-/-) mice and Cd47(-/-) mice, although being normally healthy, develop severe anemia and splenomegaly under chronic colitis, peritonitis, cytokine treatments, and CFA-/LPS-induced inflammation, owing to splenic macrophages phagocytizing self-red blood cells. Ex vivo phagocytosis assays confirmed general inactivity of macrophages from Sirp alpha(-/-) or Cd47(-/-) mice toward healthy selfcells, whereas they aggressively attack toward bacteria, zymosan, apoptotic, and immune complex-bound cells; however, treating these macrophages with IL-17, LPS, IL-6, IL-1 beta, and TNF alpha, but not IFN gamma, dramatically initiates potent phagocytosis toward self-cells, for which only the Cd47-Sirpa interaction restrains. Even for macrophages from WT mice, phagocytosis toward Cd47(-/-) cells does not occur without phagocytic activation. Mechanistic studies suggest a PKC-Syk-mediated signaling pathway, towhich IL-10 conversely inhibits, is required for activating macrophage self-targeting, followed by phagocytosis independent of calreticulin. Moreover, we identified spleen red pulp to be one specific tissue that provides stimuli constantly activating macrophage phagocytosis albeit lacking in Cd47(-/-) or Sirp alpha(-/-) mice.